The kidney plays a very important role in the regulation of phosphorus metabolism. Reduced kidney function would cause hyperphosphatemia due to the build-up of phosphorus in the body. Generally, the blood phosphorus level of a healthy individual is about 2.5 to 4.7 mg/dL. When a blood phosphorus level exceeds 5.5 mg/dL, a treatment (such as, drug administration) is needed to lower the blood phosphorus level.
In the excess phosphorus condition such as hyperphosphatemia, the production and secretion of parathyroid hormone (PTH) are increased, and the growth of accessory thyroid cells is enhanced, thereby inducing secondary hyperparathyroidism. It has been revealed that hyperphosphatemia is involved in the development of renal failure, the onset of cardiovascular complications (for example, phosphorus is bound with calcium in the blood and deposited on the arterial walls, thereby causing arteriosclerosis), and the like. It has been reported that hyperphosphatemia is not only a cause of cardiovascular disorders but also an exacerbating factor to reduce life expectancy for dialysis patients and patients with compromised renal function.
Since a positive correlation is observed between an elevation in PTH level and an increase in fractional phosphate excretion rate, this effect has been believed to be mostly due to increased PTH secretion. However, possible involvement of any components other than PTH has been presented. It has not thoroughly understood for the phosphorus metabolism. Therefore, there is currently no developed, effective blood phosphorus level lowering agent taking advantage of the function of phosphorus metabolism. The removal of phosphorus from the blood relies on dialysis for patients with renal failure who have lost their renal function.
Dialysis patients and patients with impaired renal function often undergo severe dietary restrictions to reduce the intake of phosphorus and the like. However, even with dietary restrictions, they still intake phosphorus of about 1200 mg per day. Since at most about 1000 mg of phosphorus can be removed in one dialysis session, about 3000 mg of phosphorus can be removed in 3 dialysis sessions weekly. Thus, the phosphorus intake is often excessive.
Therefore, dialysis patients and patients with impaired renal function often take a phosphate binder together with dietary restrictions in order to prevent the elevation in blood phosphorus levels. Examples of phosphate binders include those that can adsorb physically phosphorus in the intestinal tract via oral ingestion, including calcium-containing phosphate binders and calcium-free phosphate binders.
However, calcium-containing phosphate binders would lead to excessive intake of calcium to cause the calcium elevation in blood, thereby increasing a risk of cardiovascular disorders. In addition, a calcium-containing phosphate binder, when administered in conjunction with activated vitamin D, cannot be administered in a sufficient amount.
Examples of calcium-free phosphorus binders include ion-exchange resin phosphate binders as disclosed in Patent Documents 1 to 3. However, it is reported that there are side effects such as constipation, abdominal fullness, nausea, and vomiting in ion-exchange resin phosphate binders.
Furthermore, dialysis patients and patients with impaired renal function may be restricted on the intake of not only phosphorus but also potassium, salts, water, and the like. However, sufficient restriction on the intake of phosphorus is difficult in the regard of nutrient intake. Therefore, there is a demand for an effective and safe pharmaceutical preparation.
Attempts have recently been made to develop a blood phosphorus level lowering agent from food materials. Examples of such blood phosphorus level lowering agents include a preparation for hyperphosphatemia which contains as an effective ingredient a galactomannan hydrolysate composed of neutral saccharides (Patent Document 4), a blood phosphorus level lowering agent which contains chitosan oligosaccharides as an effective ingredient (Patent Document 5), and a phosphorus absorption inhibitor which contains a red-alga extract as an effective ingredient (Patent Document 6).
The preparation for hyperphosphatemia which contains as an effective ingredient a galactomannan hydrolysate as disclosed in Patent Document 4 is usually ingested with food, but it seems that the preparation is ingested with water when taken without food. Since dialysis patients are subject to the restrictions on the intake of water, the dosage form of allowing for ingestion without water is preferable to ingest the preparation for hyperphosphatemia.
The blood phosphorus level lowering agent which contains chitosan oligosaccharides as an effective ingredient as disclosed in Patent Document 5 contains oligosaccharide as the principal component, and it would not cause deteriorated mineral absorption in the large intestine. However, it is possible that such a blood phosphorus level lowering agent would cause diarrhea, dehydration, and the like.
The effective ingredient red alga of the phosphorus absorption inhibitor as disclosed in Patent Document 6 can bind strongly to potassium, calcium, iron, magnesium, sodium, and the like to absorb such minerals, which is needed for dialysis patients, thereby causing mineral deficiency. Since mineral level would be varied on dialysis, the phosphorus absorption inhibitor which can absorb minerals is required to be administered carefully for dialysis patients.
It is known that an enteric preparation containing a lactic acid bacterium is administered to reduce neutral fat, uremic substances, and the like in blood for dialysis patients (Patent Document 7). Patent Document 7 discloses that such a preparation ameliorates arteriosclerosis, and ameliorates uremia associated with chronic kidney failure by reducing indoxyl sulfate, phenol, and like substances. However, Patent Document 7 does not make any references to a blood phosphorus level.
Patent Document 8 discloses that a specific type of lactic acid bacterium accumulates phosphorus in the microbial cell in the form of polyphosphoric acid. However, any correlation is made clear in Patent Document 8 between the accumulation of polyphosphoric acid in the microbial cell and blood phosphorus level.    [Patent Document 1] Japanese Laid-Open Patent Publication No. 2001-48791    [Patent Document 2] Japanese Laid-Open Patent Publication No. 9-295941    [Patent Document 3] WO 01/068106    [Patent Document 4] Japanese Laid-Open Patent Publication No. 2007-22992    [Patent Document 5] Japanese Laid-Open Patent Publication No. 2000-344802    [Patent Document 6] Japanese Laid-Open Patent Publication No. 2001-2581    [Patent Document 7] Japanese Laid-Open Patent Publication No. 2004-277296    [Patent Document 8] Japanese Laid-Open Patent Publication No. 2006-176450